CN101633656B - Method for synthesizing candesartan cilexetil as candesartan medicament - Google Patents
Method for synthesizing candesartan cilexetil as candesartan medicament Download PDFInfo
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- CN101633656B CN101633656B CN2009101698927A CN200910169892A CN101633656B CN 101633656 B CN101633656 B CN 101633656B CN 2009101698927 A CN2009101698927 A CN 2009101698927A CN 200910169892 A CN200910169892 A CN 200910169892A CN 101633656 B CN101633656 B CN 101633656B
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Abstract
The invention relates to a preparation method of an important candesartan cilexetil intermediate, which mainly comprises the following steps: carrying out a coupling reaction on 2-ethyoxyl-1-[4'-bromobenzyl] benzimidazole-7-carboxylic ester and 2-[N-(triphenylmethyl)-tetrazole] borophenylic acid to obtain a 2-ethyoxyl-1-[[2'-(N trityl-tetrazole-5-base) diphenyl-4-base] methyl] benzimidazole-7-carboxylic ester which is the candesartan cilexetil intermediate; then hydrolyzing the intermediate to obtain candesartan cilexetil.
Description
Technical field
The invention belongs to medicine synthetic.Be specifically related to the new preparation process of Candesartan (1), and intermediate 2-oxyethyl group-1-[[2 '-(N trityl-tetrazole-5-yl) biphenyl-4-yl] methyl] preparation method of benzimidazole-7-carboxylate (8).
Background technology
Along with China's expanding economy, the raising of living standards of the people, the disease of cardiovascular aspect becomes harm China people's a kind of common high-risk disease.Angiotensin II (Ang II) acceptor inhibitor is a kind of medicine of important Cardiovarscular.After Angiotensin II (Ang II) acceptor inhibitor listing in 1994, the researchist is on the basis of its parent nucleus, to its compound structure addition, derivative, modification, constantly strengthened its hypotensive curative effect, extended action time, reduce toxic side effect, further promoted the development process of this class medicine, thereby formed the serial chemicals that is referred to as " husky smooth class ".
Sartans is the medication of hypertension first-line treatment, has brand-new Hypotensive Mechanism, and step-down steadily, good effect, long action time, patient tolerability be good.There is at present research institution carrying out the clinical study for the treatment of diabetes and heart failure, attempts to increase how new indication, to obtain larger benefit.
It is smooth that Candesartan is in sartans a kind of important biphenyl class sand.Market outlook are wide.
Common Candesartan is synthetic need to take biphenyl derivatives as the primitive reaction thing, obtain Candesartan through series reaction.As patent EP459136, CN1204125, document J.Med.Chem.1993,36,2182-2196; J.Med.Chem.1993,36,2343-2349. are wherein or biphenyl derivatives has generated the tetrazole group and then participates in reaction, or react at reaction second half section biphenyl cyano group and trinitride and obtain the tetrazole group.The former has relatively high expectations to reaction cost, and the latter is because the participation reactivity hazard of trinitride is larger.The price of biphenyl analog derivative is higher, brings cost to rise.
Summary of the invention
The present invention is mainly 2-oxyethyl group-1-[4 '-bromobenzyl] benzimidazole-7-carboxylate and 2-[N-(trityl)-tetrazole] phenyl-boron dihydroxide obtains the intermediate 2-oxyethyl group-1-[[2 ' of Candesartan-(N trityl-tetrazole-5-yl) biphenyl-4-yl through linked reaction] methyl] benzimidazole-7-carboxylate.And then obtain Candesartan through hydrolysis.
Wherein sloughing on tetrazole on protecting group and carboxyl protecting group can be undertaken by being hydrolyzed under acidic conditions.
Below content of the present invention is further explained.
At first 2-amino-3-nitro-benzoic ether and p-bromobenzaldehyde generate imines under alkaline condition, the reduction of group with imine moiety (4) is carried out in two steps, be respectively reduction imido grpup and nitro: the reductive agent of reduction imido grpup is sodium borohydride or the POTASSIUM BOROHYDRIDE of alkali metal borohydride, the calcium borohydride of alkaline-earth metal boron hydride, the sodium cyanoborohydride of basic metal cyano group hydroborate or cyano group lithium borohydride, solvent are methyl alcohol, ethanol, Virahol or the ethylene glycol of alcohols; The reduction nitro is that the reductive agent of amido is iron, zinc or the tin of metal, and the sodium polysulphide of reducing metal salt, tindichloride or S-WAT, solvent have the mixing solutions of water, water and alcohol, and alcohol used is methyl alcohol, ethanol, propyl alcohol, Virahol or ethylene glycol.Compound (5) and the tetraethyl orthocarbonate of reduction institute are reacted into compound (6) under acidic conditions.
According to the present invention, SUZUKI is coupled under alkaline condition, and catalyzer exists, by 2-oxyethyl group-1-[4 '-bromobenzyl] benzimidazole-7-carboxylate and 2-[N-(trityl)-tetrazole] phenyl-boron dihydroxide reacts and obtains intermediate (8).
SUZUKI linked reaction condition must be anhydrous and oxygen-free.Need not stop drum nitrogen in reaction comes except deoxidation.Solvent is tetrahydrofuran (THF), methylene dichloride, and toluene, dioxane, in ethyl acetate, any one, must be anhydrous solvent.Alkaline condition can be Anhydrous potassium carbonate, and anhydrous sodium carbonate is a kind of in anhydrous phosphoric acid potassium.
Catalyzer is mainly that the title complex by palladium provides, and the title complex of the present invention's palladium used is by what palladium reaction of triphenyl phosphorus, generates the triphenyl phosphorus palladium and is used as catalyzer.
N2-oxyethyl group-1-[[2 '-(N trityl-tetrazole-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate sloughs that on tetrazole and carboxyl, blocking group can obtain Candesartan, and deprotection of the present invention is mainly to remove blocking group by one kettle way.
The deprotection steps solvent is for mixing volume.The mixture of organic solvent and water specifically.Organic solvent can select tetrahydrofuran (THF), methylene dichloride, toluene, dioxane, methyl alcohol, ethanol, dimethylbenzene etc. wherein any one.Reaction conditions is acid, and the mineral acid that can adopt has hydrochloric acid, Hydrogen bromide, sulfuric acid etc.; Organic acid has methylsulfonic acid, acetic acid etc.
The invention has the advantages that: this type of traditional candesartan intermediate synthesize synthetic tetrazole group in step ground after leaning on, because the synthetic needs of tetrazole are used trinitride, reaction relatively is difficult to control.And this patent has been avoided in the end generating tetrazole in synthesis step, has safety, efficiently characteristic.
Embodiment
Embodiment 1.
Step a 2-[[4-bromobenzene] methylene is amino]-preparation of 3-nitrobenzene methyl
Add the triethylamine of 16ml to 2-amino-3-nitro-benzoic ether hydrochloride (23g) in the tetrahydrofuran (THF) of 120ml, add again anhydrous magnesium sulfate 25g, fully after stirring reaction, the p-bromobenzaldehyde that adds (18.5g) stirs, the TLC monitoring, after the question response complete reaction, separate two-phase, liquid phase is evaporated in a vacuum and dry in high vacuum, obtain flaxen oil.Need not further process next step reaction of direct input.
Step b 2-[[4-bromobenzene] methylamino]-the 3-Methyl anthranilate
Add methanol solution to be cooled to 0-5 ℃ imines in step a, add POTASSIUM BOROHYDRIDE under stirring in batches, finish, stir 30min, after TLC detection reduction reaction is completed, steam methyl alcohol, add 40ml water, regulate PH=5-6 with hydrochloric acid, suction filtration, solid washes with water, and oven dry obtains the 2-[[4-bromobenzene] methylamino]-the 3-nitrobenzene methyl.
Step c 2-[[4-bromobenzene] methylamino]-preparation of 3-Methyl anthranilate.
Add 70ml methyl alcohol in the hydrochloric acid of 150ml 2M, tin protochloride 38g, and product 2-[[4-bromobenzene in step b] methylamino]-the 3-nitrobenzene methyl.Heat to 70-80 ℃ of reaction, reaction is finished, and evaporates methyl alcohol, and regulator solution PH6-7 uses the 70ml ethyl acetate extraction, and organic phase is dry, evaporates ethyl acetate, and recrystallization gets the 2-[[4-bromobenzene] methylamino]-the 3-Methyl anthranilate.
Steps d 2-oxyethyl group-1-[[4-bromobenzene] methyl] preparation of benzoglyoxaline-7-carboxylate methyl ester
With sulfuric acid 4.9g (0.05mol), the 2-[[4-bromobenzene] methylamino]-3-Methyl anthranilate 20g and tetraethyl orthocarbonate (30ml) mixing, in 80 ℃ of stirring reactions, reaction is finished, reclaim under reduced pressure tetraethyl orthocarbonate, remaining solid are directly used in lower one-step hydrolysis reaction.
Step e 2-oxyethyl group-1-[[2 '-(N trityl-tetrazole-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate
0.5g triphenyl phosphorus is dissolved in the 500ml anhydrous tetrahydro furan, removes wherein oxygen by drum nitrogen.0.4g palladium joins mentioned solution, stirs 30min, ceaselessly rouses nitrogen in whipping process and comes deoxygenation.N-pentanoyl-N-[(4-bromine)-phenmethyl]-Valine methyl esters 8.1g; 2-[N-(trityl)-tetrazole] phenyl-boron dihydroxide 9.5g; salt of wormwood 22g drops in above-mentioned reaction solution, removes the oxygen that mixes in reaction solution, reflux 24 hours by drum nitrogen.Reaction finishes, cold filtration, and filtrate is washed with deionized water repeatedly.With the organic phase concentrating under reduced pressure, separate out solid.The gained solid is 2-oxyethyl group-1-[[2 '-(N trityl-tetrazole-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate 12.5g.
Step f 2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylic acid
Reflux condensing tube is being housed, and temperature is taken into account in churned mechanically 1000ml there-necked flask, adds the product 12g of step e, and tetrahydrofuran (THF) (600ml) and hydrochloric acid (37%, 70ml), stirring and dissolving, the adularescent solid is separated out; Be heated to 60 ℃ of left and right, reacted 0.5 hour, be cooled to room temperature, filter; Filtrate add hydrochloric acid (37%, 30ml), be heated to 80 ℃ of left and right, continue reaction 24 hours, the TLC raw material disappears substantially, stirring cools, and under 30 ℃, regulates PH=6.9-7.0, concentrating under reduced pressure with the sodium hydroxide solution of 5mol/L.Residual solution is regulated PH=2-3 with the hydrochloric acid of 2mol/L, separates out solid.Filter, solid washes with water, and vacuum-drying obtains white solid 5.6g.The gained solid is N-[[2 '-(1H-tetrazole-5-yl)-(1,1 '-phenylbenzene-4-yl)-methyl]-Valine, i.e. Candesartan.
Embodiment 2.
Step a
Produce 2-oxyethyl group-1-[[2 '-(N trityl-tetrazole-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.
0.05g four triphenyl palladium phosphorus are dissolved in the 500ml anhydrous tetrahydro furan, remove wherein oxygen by drum nitrogen.Stir 30min, ceaselessly rouse nitrogen in whipping process and come deoxygenation.N-pentanoyl-N-[(4-bromine)-phenmethyl]-Valine methyl esters 13g; 2-[N-(trityl)-tetrazole] phenyl-boron dihydroxide 15.4g; salt of wormwood 22g drops in above-mentioned reaction solution, removes the oxygen that mixes in reaction solution, reflux 24 hours by drum nitrogen.Reaction finishes, cold filtration, and filtrate is washed with deionized water repeatedly.With the organic phase concentrating under reduced pressure, separate out solid.The gained solid is 2-oxyethyl group-1-[[2 '-(N trityl-tetrazole-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate 21g.
Step b
Produce 2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) biphenyl-4-yl] methyl] benzoglyoxaline-7-carboxylic acid
Reflux condensing tube is being housed, and temperature is taken into account in churned mechanically 1000ml there-necked flask, adds the product 21g of step e, with nitrile (600ml) and sulfuric acid (25%, 70ml), stirring and dissolving, the adularescent solid is separated out; Be heated to 60 ℃ of left and right, reacted 0.5 hour, be cooled to room temperature, filter; Filtrate add hydrochloric acid (37%, 30ml), be heated to 80 ℃ of left and right, continue reaction 24 hours, the TLC raw material disappears substantially, stirring cools, and under 30 ℃, regulates PH=6.9-7.0, concentrating under reduced pressure with the potassium hydroxide solution of 5mol/L.Residual solution is regulated PH=2-3 with the hydrochloric acid of 2mol/L, separates out solid.Filter, solid washes with water, and vacuum-drying obtains white solid 9g.The gained solid is N-[[2 '-(1H-tetrazole-5-yl)-(1,1 '-phenylbenzene-4-yl)-methyl]-Valine, i.e. Candesartan.
Claims (6)
1. the synthetic method of a candesartan cilexetil as candesartan medicament, it is characterized in that: reactions steps is: 2-amino-3-nitro-benzoic ether 2 generates group with imine moiety 4 with p-bromobenzaldehyde 3 under alkaline condition, group with imine moiety 4 is carried out reduction reaction, what obtain after reduction reaction 5 is reacted into 2-oxyethyl group-1-[4 '-bromobenzyl again under acidic conditions with tetraethyl orthocarbonate] benzimidazole-7-carboxylate 6, 6 with 2-[N-(trityl)-tetrazole] phenyl-boron dihydroxide generates 2-oxyethyl group-1-[[2 '-(N trityl-tetrazole-5-yl) biphenyl-4-yl through the SUZUKI linked reaction] methyl] benzimidazole-7-carboxylate 8, 8 prepare Candesartan at last through the blocking group of sloughing on tetrazole and carboxyl, reaction equation in each step is as follows:
Reaction formula 1 wherein R ' is carboxyl-protecting group.
2. according to claim 1 a kind of synthetic method of candesartan cilexetil as candesartan medicament, it is characterized in that: described reduction reaction is carried out in two steps, respectively with reductive agent reduction imido grpup and nitro.
3. the synthetic method of a kind of candesartan cilexetil as candesartan medicament according to claim 2, it is characterized in that: the reductive agent of reduction imido grpup is sodium borohydride or the POTASSIUM BOROHYDRIDE of alkali metal borohydride, the calcium borohydride of alkaline-earth metal boron hydride, the sodium cyanoborohydride of basic metal cyano group hydroborate or cyano group lithium borohydride, solvent are methyl alcohol, ethanol, Virahol or the ethylene glycol of alcohols; The reductive agent of reduction nitro is iron, zinc or the tin of metal, sodium polysulphide, tindichloride or the S-WAT in reducing metal salt, and solvent is the mixing solutions of water, water and alcohol, and alcohol used is methyl alcohol, ethanol, propyl alcohol, Virahol or ethylene glycol.
4. the synthetic method of a kind of candesartan cilexetil as candesartan medicament according to claim 1, it is characterized in that, 6 and 7 generate 2-oxyethyl group-1-[[2 '-(N trityl-tetrazole-5-yl) biphenyl-4-yls through SUZUKI linked reactions] methyl] the SUZUKI linked reaction that occurs during benzimidazole-7-carboxylate 8 is to occur existing under the condition of catalyzer.
5. the synthetic method of according to claim 1 or 4 described a kind of candesartan cilexetil as candesartan medicament, it is characterized in that: described SUZUKI linked reaction solvent is tetrahydrofuran (THF), methylene diethyl ether, methylene dichloride, toluene, any one in dioxane; The triphenyl phosphorus palladium that triphenyl phosphorus and palladium reaction generate is as the catalyzer of reaction; Whole reaction needed is carried out under the condition of anhydrous and oxygen-free, and comes deoxidation by drum nitrogen.
6. the synthetic method of a kind of candesartan cilexetil as candesartan medicament according to claim 1, it is characterized in that: the solvent of sloughing the protecting group on tetrazole and carboxyl is the mixture of organic solvent and water, and wherein organic solvent is any one in tetrahydrofuran (THF), methylene dichloride, toluene, dioxane, methyl alcohol, ethanol, dimethylbenzene; Reaction conditions is acid, and organic acid or mineral acid provide acidic conditions, and described mineral acid is hydrochloric acid, Hydrogen bromide or sulfuric acid; Described organic acid is methylsulfonic acid or acetic acid.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101068807A (en) * | 2004-12-16 | 2007-11-07 | 通益制药有限公司 | Method for production of candesartan |
| ES2300175A1 (en) * | 2006-02-14 | 2008-06-01 | Inke, S.A. | Method for obtaining intermediate, particularly candesartan used in preparation of active pharmaceutical compound, particularly candesartan cilexetil for treatment of hypertension or heart failure, involves forming diphenyl bond |
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| CN101068807A (en) * | 2004-12-16 | 2007-11-07 | 通益制药有限公司 | Method for production of candesartan |
| ES2300175A1 (en) * | 2006-02-14 | 2008-06-01 | Inke, S.A. | Method for obtaining intermediate, particularly candesartan used in preparation of active pharmaceutical compound, particularly candesartan cilexetil for treatment of hypertension or heart failure, involves forming diphenyl bond |
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